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Disease Chromosome Gene Product Inheritance MutationSCA1 6p23 ataxin-1 AD CAG in coding region SCA2 12q24.1 ataxin-2 AD CAG in coding region SCA3 14q21 ataxin-3 AD CAG in coding region SCA4 16q22.1 ? AD ? SCA5 11 ? AD ? SCA6 19p13.1-2 a1A voltage-dependent calcium channel subunit AD CAG in coding region SCA7 3p21.1-p12 ataxin7 AD CAG in coding region SCA8 13q21 ? AD Untranslated CTG repeat on antisense strand SCA10 22q13 ataxin-10 AD Intronic ATTTC repeat SCA11 15q14-21 ? AD SCA12 5q31 protein AD CAG in 5' UTR region phosphatase 2A SCA13 19q13 ? AD ? SCA14 19q13.4 ? AD ? SCA15 3pter-24.2 ? AD ? SCA16 8q22.24 ? AD ? SCA17 6q27 TATA-binding protein AD CAG in coding region FA 9q13-21 frataxin-1 AR Intronic GAA repeat Ataxia-telangiectasia 11q22-23 ATM AR Point mutations Friedreich Ataxia This is an autosomal-recessive progressive illness, generally beginning in the first decade of life with gait ataxia, followed by hand clumsiness and dysarthria. Deep tendon reflexes are depressed or absent, but an extensor plantar reflex is typically present. Joint position and vibratory sense are impaired, and there is sometimes loss of pain and temperature sensation and light touch. Most patients develop pes cavus and kyphoscoliosis. There is a high incidence of cardiac disease with arrhythmias and congestive heart failure. Concomitant diabetes is found in about 10% of patients. Most patients become wheelchair-bound within about 5 years of onset; the cause of death is intercurrent pulmonary infections and cardiac disease. The gene for Friedreich ataxia has been mapped to chromosome 9q13, and in most cases, there is a GAA trinucleotide repeat expansion in the first intron of a gene encoding a protein named frataxin.[218] Affected individuals inherit abnormal forms of the frataxin gene from both parents and have extremely low levels of the protein. In some cases of Friedreich ataxia, one of the mutant alleles harbors a missense or nonsense mutation. Frataxin undergoes processing and ends up in the inner mitochondrial membrane, where it has been suggested to play a role in regulation of iron levels.[219] [220] Because of the need for this metal in many of the complexes of the oxidative phosphorylation chain, mutations in frataxin have been suggested to result in generalized mitochondrial dysfunction. Thus, Friedreich ataxia shares biologic features with other spinocerebellar ataxias (anatomic distribution of pathology, trinucleotide repeat expansion) and the mitochondrial encephalopathies. Morphology. The spinal cord shows loss of axons and gliosis in the posterior columns, the distal portions of corticospinal tracts, and the spinocerebellar tracts. There is degeneration of neurons in the spinal cord (Clarke column), the brainstem (cranial nerve nuclei VIII, X, and XII), the cerebellum (dentate nucleus and the Purkinje cells of the superior vermis), and to some extent the Betz cells of the motor cortex. Large dorsal root ganglion neurons are also decreased in number; their large myelinated axons, traveling first in the dorsal roots and then in dorsal columns, therefore undergo secondary degeneration. The heart is enlarged and may have pericardial adhesions. Multifocal destruction of myocardial fibers with inflammation and fibrosis is detectable in about half the patients who come to autopsy examination. Date: 2016-04-22; view: 811
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